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Marianne Hokland

Publications and source records attributed to Marianne Hokland.

18 recordsLinked to original sources
PubMed2006

Interleukin-21 mRNA expression during virus infections.

Interleukin-21 is a cytokine with profound impact on the proliferation and differentiation of activated leukocytes of both the innate and adaptive immune system. In experiments in vitro, antigen activation induces IL-21 production in CD4+ T cells. Where, when, and how the proliferative and activational effects of IL-21 on different leukocytes come into play in vivo in an immune response has so far not been fully investigated. We show here for the first time in vivo, that IL-21 mRNA is produced in the spleen when mice are challenged with herpes simplex virus type 2 (HSV-2) or lymphocytic choriomeningitis virus (LCMV). We show in HSV-2 challenged mice that this production takes place in CD4+ T cell fractions and is absent in CD4+ T cell-depleted fractions. We also show that the peak of IL-21 mRNA production in both the HSV-2 and LCMV-challenged mice coincides with the onset of the adaptive immune response. Thus, our data suggest a role for IL-21 in the early stages of adaptive immune response against virus infections.

Animals↗
PubMed2006

Tumour-associated macrophages are related to progression in patients with metastatic melanoma following interleukin-2 based immunotherapy.

The aim of the present study was to analyze whether leukocyte subsets in peripheral blood and tumour biopsies obtained before treatment were able to predict response or survival in patients with metastatic melanoma following Interleukin-2 (IL-2) based immunotherapy. Flow cytometry was performed on peripheral blood for CD4(+) T cells, CD8(+) T cells and CD56(+) natural killer (NK) cells. Immunohistochemical analyses were used to identify CD4(+) T cells, CD8(+) T cells, CD57(+) NK cells and CD64(+) (macrophages) cells in tumour biopsies. High numbers of tumour-associated CD64(+) macrophages in tumour biopsies were statistically significantly associated with poor response to treatment. Our data suggest that tumour-associated macrophages may correlate negatively with response, which may be of biological importance for IL-2 based immunotherapy of malignant melanoma.

Adult↗
PubMed2006

Infusion of hypertonic saline (7.5%) does not change neutrophil oxidative burst or expression of endothelial adhesion molecules after abdominal hysterectomy.

BACKGROUND: Previous studies found hypertonicity to affect neutrophils in intact laboratory animals and in human blood cell cultures. We investigated whether infusion of hypertonic saline in a clinical relevant dose before hysterectomy affected peripheral blood neutrophils and their response to surgery. METHODS: Fifteen women scheduled for open abdominal hysterectomy were randomized double-blindly to infusion of 4 mL/kg 7.5% NaCl, 4 mL/kg 0.9% NaCl, or 32 mL/kg 0.9% NaCl over 20 minutes. Blood was collected at baseline, after infusion, 1, 4, and 24 hours postoperatively for the determination of leukocyte and differential count, neutrophil membrane expression of endothelial adhesion molecules by flow cytometry, and O2- -generation by superoxide dismutase-inhibitable reduction of cytochrome C. RESULTS: Surgery induced well-known changes in the number and distribution of white blood cells, reduced the expression of adhesion molecules, and halved the superoxide production unrelated to the tonicity or volume of the infused fluids. CONCLUSION: Infusion of a clinically relevant dose of hypertonic saline has no detectable effect on the membrane expression of endothelial adhesion molecules or O2- -generation in circulating neutrophils after elective abdominal hysterectomy.

Adult↗
PubMed2004

Fas ligand expression in metastatic renal cell carcinoma during interleukin-2 based immunotherapy: no in vivo effect of Fas ligand tumor counterattack.

PURPOSE: It has been hypothesized that tumor cells expressing Fas ligand (FasL) might be able to counterattack and neutralize tumor-infiltrating lymphocytes. We assessed the effect of FasL tumor counterattack on the clinical outcome of interleukin-2 (IL-2)-based immunotherapy in metastatic renal cell carcinoma. EXPERIMENTAL DESIGN: Tumor core needle biopsies were obtained before IL-2-based immunotherapy in 86 patients and repeated within the first cycle in 57 patients. Tumor cells expressing FasL and intratumoral lymphocyte subsets expressing CD4, CD8, CD56, and CD57 were analyzed by immunohistochemistry. RESULTS: At baseline, negative FasL staining in tumor cells was seen in 10 of 86 (12%) biopsies, whereas intense FasL staining was seen (a) in fewer than 10% of tumor cells in 26 (30%) biopsies; (b) in 11 to 50% of tumor cells in 25 (29%) biopsies; (c) in 51 to 90% of tumor cells in 18 (21%) biopsies; and (d) in >90% of tumor cells in 7 (8%) biopsies. On treatment, tumor FasL expression did not change from baseline levels. Moreover, tumor FasL expression was not correlated with objective response or survival whereas the absolute number of CD4(+), CD8(+), CD56(+), and CD57(+) cells per mm(2) tumor tissue at baseline was significantly higher in responding patients compared with nonresponding patients (P = 0.01, P = 0.008, P = 0.015, and P < 0.001, respectively). During the first course of immunotherapy, the absolute number of CD4(+), CD8(+), and CD57(+) cells per mm(2) tumor tissue was significantly higher in responding patients compared with nonresponding patients (P = 0.034, P < 0.001, and P < 0.001, respectively). However, no correlation was observed between the number of intratumoral lymphocytes and tumor FasL expression level. CONCLUSION: These observations do not support the hypothesis that FasL tumor "counterattack" has an effect on the clinical outcome in metastatic renal cell carcinoma during IL-2-based immunotherapy.

Adult↗
PubMed2004

Leukocyte orchestration in blood and tumour tissue following interleukin-2 based immunotherapy in metastatic renal cell carcinoma.

With the objective of evaluating leukocyte orchestration in situ, serial blood samples and tumour tissue core needle biopsies were obtained at baseline and repeated after 1 month of therapy, among 49 consecutive single-institution patients with metastatic renal cell carcinoma (mRCC). Patients were treated with outpatient low-dose subcutaneous interleukin 2 (IL-2) and interferon alpha (IFN-alpha) alone (n = 23) or in combination with histamine dihydrochloride (n = 26). Objective responses were achieved in ten of 49 patients (20%) with an overall median survival of 14 months and an estimated 1- to 4-year survival rate of 57, 35, 24 and 22%, respectively. Toxicity was mild to moderate with no treatment-related deaths. High numbers of blood monocytes and neutrophils were significantly correlated to short survival. By contrast, high numbers of intratumoural CD3+, CD4+, CD8+ and CD57+ lymphocytes were positively correlated to objective response and/or long-term survival. Intratumoural lymphocytes showed low zeta expression, whereas blood lymphocytes showed almost normal levels of zeta expression. Neutrophils, the most frequent peripheral blood leukocyte subset, were scarce within the tumour tissue. Intratumoural eosinophils were not observed. In progressing patients, both the absolute number and the relative composition of leukocyte subsets in blood and tumour tissue remained unaffected by cytokine therapy. However, in responding patients, cytokine therapy was followed by an absolute and relative increase in T cells in blood as well as tumour tissue, an absolute and relative reduction in neutrophils in peripheral blood and a relative reduction of intratumoural macrophages. Histamine did not influence levels of intratumoural or blood leukocyte numbers, zeta-chain expression or cytotoxicity. In conclusion, the present regimen of outpatient low-dose subcutaneous IL-2 and IFN-alpha in mRCC should attract interest based on response, survival and toxicity. In responding patients, cytokine therapy was followed by substantial changes in the blood and tumour tissue leukocyte composition, correlated to response and survival. No discernable differences in immunologic parameters studied could be detected between histamine- and nonhistamine-treated patients.

Adult↗
PubMed2004

Detection of circulating tumor lysate-reactive CD4+ T cells in melanoma patients.

PURPOSE: We wanted to study whether an allogeneic melanoma lysate would be a feasible stimulatory antigen source for detection of a peripheral CD4+ T-cell immune response in patients with medically untreated malignant melanoma. The lysate was produced from a melanoma cell line (FM3.29) which expresses high amounts of melanoma antigens. METHODS: Fresh peripheral blood was incubated with and without lysate for 6 h in the presence of anti-CD28/anti-CD49d MoAb (for costimulation). After flow cytometric estimation of the frequency of CD69+/IFN-gamma+ cells in the CD4+ population, the response to lysate was calculated as the difference between the number of activated IFN-gamma-producing CD4+ cells in the lysate-stimulated and the nonstimulated sample. RESULTS: An immune response to lysate was observed in blood samples from 11 of 15 patients (73%) with metastatic melanoma. A weak response was found in 1 of 4 patients radically operated for localized disease, whereas no responders were seen among 7 healthy donors. The fraction of circulating lysate-activated T cells ranged from 0.0037% to 0.080% of the CD4+ population. A negative result of the assay was found occasionally, especially in donors with high background levels of spontaneous IFN-gamma production, indicating an inhibitory effect of the lysate. CONCLUSIONS: This method for detection of a peripheral T-cell immune response in melanoma patients has several advantages for clinical use. The tumor lysate preparations may contain large numbers of stimulating antigens (known, as well as unknown) and are easily prepared and handled. Potentially, the assay might be useful as a diagnostic tool, a marker of residual or recurrent disease, a prognostic factor, or a predictor or monitor of the effect of antineoplastic therapy including immune-modulating therapy.

Adult↗
PubMed2004

Tumour burden and interleukin-2 dose affect the interaction between low-dose total body irradiation and interleukin 2.

Low-dose total body irradiation (LTBI) has a synergistic immune-mediated antitumour effect when used in combination with interleukin 2 (IL-2) in a murine metastatic malignant melanoma model. To optimise the use of this combination treatment this study was performed to test the effect of tumour burden and dose of both LTBI and IL-2 on the therapeutic potential of this treatment strategy. Ten-week-old female C57BL/6 mice were inoculated intravenously (day 0) with 1 million B16F1 malignant melanoma cells. Groups of mice received no treatment, a single fraction of LTBI alone, IL-2 treatment alone, or a combination of LTBI and IL-2. Two doses of LTBI and IL-2 were tested. LTBI was given on day +10 and IL-2 treatment started on day +11. On day +18 the mice were killed. The lungs were removed and analysed for tumour burden. Lung sections were also tested for infiltrating leucocytes using immunohistochemical staining. In one experiment, mice were treated at day +7 with low-dose IL-2 with and without LTBI. LTBI (in the two tested doses) showed no independent therapeutic effects. An IL-2 dose of 300,000 Cetus units (CU) that was effective and showed synergism with LTBI when mice were treated on day +7 failed to show a therapeutic effect when mice were treated on day +10, at which time the initial tumour burden had doubled. High-dose IL-2 (600,000 CU), in contrast, led to a significant reduction in metastatic burden compared to the control group. Combining high-dose IL-2 with LTBI led to a further significant reduction in tumour burden. Moreover, this combination was associated with a less severe vascular leakage syndrome compared to IL-2 alone. IL-2 and combination treatment was associated with an increase in the number of tumour-infiltrating immune cells, but only the number of tumour-infiltrating natural killer cells reflected therapeutic efficacy. It was concluded that tumour burden at the time of treatment and IL-2 dose are two crucial factors affecting the synergism between LTBI and IL-2. The combination may not only be more effective than IL-2 alone but also less toxic.

Animals↗
PubMed2004

Is there an association between rumination and self-reported physical health? A one-year follow-up in a young and an elderly sample.

Cross-sectional studies have suggested an association between rumination and subjective health. The aim of the present study was to investigate in a longitudinal design whether rumination was related to self-reported physical health. A total of 96 young (age range 20-35) and 110 elderly (age range 70-85) participants completed questionnaires measuring rumination, negative affect, life events, and self-reported physical health at baseline and at 1-year follow-up. Multiple linear regressions showed a significant association between self-reported physical health at time I only for the elderly and negative affect mediated the association. At follow-up, rumination was significantly associated with self-reported physical health only for the young and the association was only partly mediated by negative affect. In conclusion, rumination is associated with poorer self-reported physical health, but the association depends on the age of the individual as well as time span studied.

Adaptation, Psychological↗
PubMed2004

Immunohistochemical characterisation of the local immune response in azoxymethane-induced colon tumours in the BDIX inbred rat strain.

The aim of the present study was to characterise the local immune response in a chemically induced colon tumour model in the rat. Elucidating the character of the immune reaction may contribute to optimizing immunotherapeutic regimens for colon carcinoma in this model. Colon cancer was induced by four weekly subcutaneous azoxymethane injections in inbred rats of the BDIX/OrlIco strain in two separate studies. Azoxymethane-induced tumours show many similarities to spontaneously occurring human colon carcinomas with respect to histopathological appearance. In our studies, the overall inflammatory reaction of the submucosa below the tumour was evaluated in haematoxylin-eosin-stained tissue sections. Phenotypic characterization of leukocyte infiltration in the tumour tissue was performed by immunohistochemical staining using antibodies detecting various leukocyte subsets, i.e. T cells, natural killer cells, macrophages/monocytes, and dendritic cells. The results showed that the azoxymethane-induced colon tumours were strongly infiltrated by macrophages. Furthermore, the tumours showed a moderate degree of infiltrating CD4-positive cells. Very few natural killer, CD8-positive T cells and dendritic cells (identified by the OX62 antibody) were seen in the tumour tissue. Virtually no CD25-positive cells were found. This immunohistochemical characterisation of the tumour-infiltrating immune response in this rat model could form the basis for studies aimed at developing new immunotherapeutic regimens for human colon cancer.

Animals↗
PubMed2003

NK cells and the tumour microenvironment: implications for NK-cell function and anti-tumour activity.

Although it is clear that natural killer (NK) cells have the ability to recognize and kill tumour cells in vitro, their potential as a highly effective treatment for tumours has not yet been realized in the clinical setting. Following activation, endogenous and adoptively transferred NK cells can be found in tumours. However, not all tumours are equally well-infiltrated, and many of the infiltrating cells do not make target-cell contact but rather reside in the tumour stroma. New insights into the migration of NK cells, their activation status and production of matrix-degrading proteases might help to overcome this localization defect, with implications for the treatment of human cancer.

Adoptive Transfer↗
PubMed2003

Expression levels of hsc70 and hsp60 are developmentally regulated during B-cell maturation and not associated to childhood c-ALL at presentation or relapse.

Heat shock proteins are potent regulators of apoptosis, and so they may also be involved in normal cellular differentiation and cancerogenesis. We used quantitative two-dimensional gel electrophoresis for determining whether either the constitutive chaperonic heat shock cognate protein 70 (hsc70) or heat shock protein 60 (hsp60) contribute to B-cell differentiation and leukemogenesis. We compared the expression of these hsps in normal peripheral blood (PB) CD19+ B-cells, in pediatric bone marrow (BM) CD19+ CD10+ B-cell precursors (BCPs) from normal donors, and in BCPs from common acute lymphoblastic leukemia (c-ALL) patients at diagnosis and at relapse. We found that the mean levels of hsc70 in c-ALL BCPs at initial presentation and at relapse failed to differ significantly. Likewise, they failed to differ significantly from the level in high-expressing normal BM BCPs or from that in low-expressing PB B-cells. Mean levels of hsp60 expression in c-ALL BCPs at initial presentation and at relapse were similar and not distinguishable from that in normal BM BCPs, however, elevated (by a factor of 2-3) compared with that in PB B-cells. Hsc70 and Hsp60 expressions were increased (by a factor of 2 of mean levels) in populations of normal BM BCPs as compared with populations of PB B-cells. Thus, no abnormal levels of hsc70 and hsp60 were detectable in populations of pediatric c-ALL BCPs neither at diagnosis nor at relapse. In contrast, our data were in support of developmentally regulated levels of hsc70 and hsp60 expression during B-cell ontogenesis.

B-Lymphocytes↗
PubMed2003

Phenotypic characterisation of porcine counterparts of human NK cell populations--implications for pre-clinical studies.

The phenotype of cryopreserved crossbred porcine PBMC, with special emphasis on NK cell related surface markers, was characterised. The phenotype expressed prior to stimulation with rHu IL2 and rHu IL12 was related to the in vitro cytotoxic capacity estimated in a 4-h or 21-h 51Cr-release assay. PBMC incubated in growth medium without addition of cytokines were used to investigate the spontaneous cytotoxic capacity. The results of this study suggest that crossbred porcine PBMC comprise a specific subset expressing the phenotype CD2+CD3-CD4-CD8+SWC3-CD16+CD21-. No spontaneous cytotoxicity of the PBMC could be estimated, but the expression of CD16 seems to be a basic marker of the cytokine induced cytotoxic activity. This study suggests that cryopreserved porcine PBMC can be used when possible influences on the porcine NK cell system are investigated in relation to disease models conducted experimentally in crossbred pigs.

Animals↗
PubMedDate not supplied

Low-dose total body irradiation augments the therapeutic effect of interleukin-2 in a mouse model for metastatic malignant melanoma.

BACKGROUND: Low-dose total body irradiation (LTBI) is known for its antitumor immune modulatory effects. Moreover, there is theoretical ground suggesting that combining LTBI with interleukin-2 (IL-2) will have a synergistic immune-mediated antitumor effect. However, the use of LTBI in combination with IL-2 or other forms of immunotherapy has not been tested before. AIM OF THE WORK: To test the efficacy of combining LTBI and IL-2 in controlling lung metastases in a murine model for malignant melanoma compared to IL-2 alone. MATERIAL AND METHODS: Ten-week-old female C57BL/6 mice were inoculated intravenously (on day 0) with 1 million B16F1 malignant melanoma cells. The mice received either no treatment (control group), LTBI alone (single fraction of 0.75 Gy), IL-2 treatment alone (30,000 CU x 2 daily for 5 consecutive days), or a combination of LTBI and IL-2. LTBI was given on day +7 and IL-2 treatment started day +8. On day +14, the mice were sacrificed and the lungs were removed and analyzed for tumor burden. Lung sections were also tested for tumor-infiltrating cells using immunohistochemical staining. Peripheral blood and splenic cells were collected and tested for the percentage of the various lymphocytic subsets using immunostaining and flow cytometry. RESULTS: Tumor burden expressed as the percentage of lung area occupied with metastases (+/- 1 SD), was the same in the control group (8.1 +/- 4.9%), and in the group receiving LTBI alone (8.3 +/- 4.5%). Tumor burden was reduced to 6.4% (+/- 3.4%) in the IL-2 alone group (P = 0.3) and further reduced to 3% (+/- 1%) in the combined treatment group (P = 0.004). The difference in tumor burden between the IL-2 alone group and the combined treatment group was statistically significant (P = 0.006). The combined treatment caused a significant increase in the number of natural killer (NK) cells and macrophages infiltrating the metastatic sites. This was associated with a significant increase in the percentage of CD122+ (IL-2R beta) cells and NK cells in both peripheral blood and spleens. CONCLUSION: We conclude that combining LTBI and IL-2 treatment is synergistic and therapeutically more effective than IL-2 alone. The data points to NK cells and macrophages as likely major effectors of the synergistic outcome of the combined treatment. This observation may have important clinical implications in the treatment of patients with metastatic malignant melanoma.

Animals↗
PubMedDate not supplied

Negative thoughts and health: associations among rumination, immunity, and health care utilization in a young and elderly sample.

OBJECTIVE: In the present study, it was tested whether rumination-negative, recurrent thoughts-would be associated with immune parameters and health care utilization. Because rumination has been associated with sadness and subjective sleep quality, it was tested whether these factors mediated the possible effects of rumination. A young sample and an elderly sample were included to test for age differences in the association between rumination and health-related measures. METHODS: A representative sample of 196 young subjects (20 to 35 years) and 314 elderly subjects (70 to 85 years) completed questionnaire measures of rumination, sadness, and subjective sleep quality. Immune measures included leukocyte counts, lymphocyte subsets, natural killer cell activity, and T-cell proliferation. Contacts with primary care physicians were registered for 1 year through central registers. RESULTS: Rumination displayed a positive association with total leukocyte count, total lymphocyte count, and number of B cells among the elderly, and this was not mediated by sadness or subjective sleep quality. Rumination was also positively associated with number of telephone consultations during the follow-up for the elderly, and this was partly mediated by sadness and subjective sleep quality. Although total leukocyte counts correlated with number of telephone consultations at the follow-up, none of the immune parameters mediated the association between rumination and health care utilization. No significant associations were found for the young participants. CONCLUSION: The results suggest that rumination may be associated with health-related measures in the elderly. Thus, negative thoughts may be detrimental to health, independently of negative affect.

Adaptation, Psychological↗
PubMedDate not supplied

Quantitative evaluation of the murine B16 melanoma tumor model after gene marking with an EGFP/Neo expressing retroviral vector.

Reliable evaluation of tumor growth in animal models depends upon accurate identification of all malignant cells in affected organs. An ideal tumor cell label is non-toxic, labels the cells in a population uniformly and does not affect their biological behavior. A good candidate for such a cell label is enhanced green fluorescence protein (EGFP). However, the stability of EGFP expression and the characteristics of EGFP-marked tumors cells in vivo have not yet been elucidated in detail. We here report that a B16 murine melanoma subline stably transduced with an EGFP/Neo encoding retroviral vector display the same growth patterns in vitro and in vivo as the parental cell line. Furthermore, the transduced cells were found to maintain the level of EGFP expression in vivo for at least 15 days. Thus, B16 malignant melanoma cells stably transduced with the gene for EGFP seem well suited for studies on tumor growth in mouse models.

Animals↗
PubMedDate not supplied

Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride.

Interleukin-2 and interferon-alpha are pleiotropic immuno-activating cytokines with clinical efficacy in malignant melanoma. The anti-melanoma activity of these cytokines is believed to result from the triggering of lymphocyte-mediated killing of tumour cells. In ongoing clinical trials, histamine dihydrochloride is used as an adjuvant to IL-2 and IFN-alpha with a view to protecting lymphocytes from oxidative inhibition induced by tumour-infiltrating monocyte/macrophages. In this study, we have serially monitored mononuclear cells in peripheral blood and tumour biopsies from 13 patients with metastatic malignant melanoma treated under a protocol comprising histamine, IFN-alpha and low-dose IL-2. One complete and 3 partial responses were observed, while 3 patients had stable disease and 6 progressed. A trend towards a gradual increase in the absolute number of circulating CD56+/CD3- NK cells in patients maintaining stable disease during therapy was noted. In tumour tissues, the extent of leukocyte infiltration prior to treatment correlated with tumour response. Additional infiltration by NK cells (CD56+) and monocytes during treatment was seen only in responding patients. Patients with progressive disease exhibited a low density of leukocytes infiltrating tumour tissues at the onset of treatment as compared to the surrounding tissues. Our data indicate that the degree and localization of mononuclear infiltration before and during immunotherapy under this protocol may determine therapeutic anti-tumour responses.

Adult↗